Calpains are a class of ubiquitously expressed calcium-dependent cysteine proteases that regulate numerous intracellular signaling cascades and are fundamentally involved in regulating protein kinases responsible for cytoskeletal dynamics and remodeling. Under physiological conditions, transient and localized Ca2+ fluxes from extracellular or intracellular calcium stores result in controlled activation of local calpain populations. Once activated, calpains are tightly regulated by a selective endogenous peptidyl inhibitor, calpastatin (CAPN). While regional calpain proteolytic activity is essential for native Ca2+ signaling and cytoskeletal remodeling, pathological conditions may produce excessive levels of Ca2+, resulting in widespread calpain activation and unregulated proteolysis leading to exacerbation of pathological conditions. Hyperactivation of calpain 1 is implicated as a primary or secondary pathological event in a wide range of afflictions and neurodegenerative states, including Alzheimer's Disease. Calpain 1 is primarily localized in synapses, and is abnormally activated in post mortem brains of Alzheimer's Disease patients, while calpastatin is found in significantly low amounts.
Alzheimer's Disease (AD) is a progressive and terminal condition characterized by debilitating memory loss and extensive deterioration of cognitive and functional abilities. Currently available therapies for AD are palliative and do not decelerate or arrest progression of the disease. Cholinesterase inhibitors such as Razadyne® (galantamine), Exelon® (rivastigmine), Aricept® (donepezil), and Cognex® (tacrine) have been prescribed for early stages of AD, and may temporarily delay or halt progression of symptoms. However, as AD progresses, the brain loses less acetylcholine, thereby rendering cholinesterase inhibitors ineffective. Namenda® (memantine), an N-methyl D-aspartate (NMDA) antagonist, is also prescribed to treat moderate to severe Alzheimer's disease; however only temporary benefits are realized.
There is a need for novel calpain inhibitors. There is also a need for novel treatments for a variety of disease states for which calpain 1 is implicated.